Epidemiology
Non-Hodgkinís lymphomas (NHLs) are a very heterogeneous group of cancers that develop in the lymph nodes present throughout the body. There are over 25 subtypes of NHL, although most are diagnosed infrequently. Lymphoplasmacytic lymphoma is one of those rare subtypes, accounting for only 1 to 2% of all NHLs.
This lymphoma arises from plasma cells, which are mature B-lymphocytes. It is most often associated with an increased IgM protein produced by the lymphoma cells and is commonly referred to as Waldenstrom’s macroglobulinemia (WM), after the Swedish physician who first described the syndrome in 1944. WM is considered an indolent lymphoma; the disease progresses very slowly, and patients tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and although WM responds well to a variety of chemotherapy drugs, it is generally considered to be incurable. WM is somewhat more common in men compared to women, and it is much more common in white patients than in African-Americans. The average age at diagnosis is between 60 and 65 years.
Risk Factors
The most important risk factor for WM is monogamopathy of unknown significance (MGUS). This is the asymptomatic presence of an elevated serum protein. These patients are more than 40 times more likely to develop WM than the general population, and as well, have a significantly increased risk of multiple myeloma. Other less important risk factors for the development of WM include a family history, occupational exposure to paints, rubber dyes and leather manufacturing, and infection with the hepatitis C virus.
Signs and Symptoms
WM presents with a wide array of signs and symptoms. These can broadly be categorized as due to lymphoma infiltration of organs, due to IgM protein circulating in the blood, and as a result of tissue deposition and the autoimmune activity of the IgM protein.
Lymphoma infiltration of organs commonly leads to enlarged lymph nodes (lymphadenopathy), as well as enlarged liver and/or spleen. Bone marrow involvement by WM is almost universal, causing anemia in 80% of patients. Low platelet count and low white blood cell count may occur due to bone marrow infiltration as well. These common signs lead to complaints of fever, fatigue, and abdominal pain in patients. Pulmonary nodules are occasionally seen due to lymphoma infiltration of the lung tissue, but they usually do not cause symptoms.
IgM circulating in the blood also causes several complications. IgM is a large molecule. When its levels are very high, as in WM, it can lead to increased thickness of the blood (or hyperviscosity). This occurs in up to 15 to 20% of patients with WM. Hyperviscosity syndrome may cause neurologic symptoms, such as headache and visual changes. Rarely it can lead to heart failure or stoke. IgM also interferes with the normal functioning of blood clotting factors and platelets. This often causes chronic mild nosebleeds and bleeding from the gums. Finally, the IgM protein can also precipitate in colder temperatures, leading to cyroglobulinemia. Symptoms of this are present in 5% of WM patients and include joint aches, numbness/tingling in the hands and feet, small bruises, and skin ulcers.
The excessive IgM protein can deposit in many tissues, including the kidneys, intestines, and skin. This leads to common presenting symptoms such as diarrhea and protein in the urine. Kidney failure, however, is uncommon. More rarely, deposition may occur in the heart, liver, and lungs. The IgM protein also leads to a variety of autoimmune processes. This may include autoimmune hemolytic anemia in less than 10% and peripheral neuropathies in up to 15%. Schnitzler syndrome is an autoimmune complication of elevated IgM levels that leads to fever, itchy skin lesions, and joint aches.
Diagnosis and Staging
WM is often confused with multiple myeloma, which also has a characteristic elevated serum protein. Unlike myeloma, clinically, WM does not cause lytic bone lesions and much less commonly causes renal failure and hypercalcemia. Diagnostically, in the hands of an experienced hematopathologists, a bone marrow biopsy and serum protein electropheresis (SPEP) can differentiate the two malignancies. A bone marrow biopsy shows the characteristic lymphoplasmyctic cells, and an SPEP measures the amount of IgM protein in the blood.
Once the diagnosis of WM is established by bone marrow biopsy and SPEP, patients should undergo additional tests to determine the extent of disease. This should include CT scans of the abdomen and pelvis, a complete blood count, and serum chemistries (including lactate dehydrogenase (LDH) and uric acid). Beta-2-microglobulin is a tumor marker that is often increased in proportion to the extent of tumor. This should be measured at the time of diagnosis and used to monitor response to therapy. A 24-hour urine collection should be done to measure the amount of protein in the urine, which indicates the extent of kidney damage done by the IgM protein. Serum viscosity should also be measured to detect early hyperviscosity syndrome. Finally, coagulation studies should be done, as the IgM protein can interfere with blood clotting factors. There is no formal staging system for WM.
Prognostic Factors
The average survival time for a patient with WM is between 5 and 10 years. Risk factors that lead to the shorter end of that average survival range include age greater than 65 years, anemia, low platelet count (thrombocytopenia), very high beta-2-microglobulin, and very high IgM serum concentration. Low risk patients are those with fewer than two of these factors, not including age. Intermediate risk patients have two risk factors OR are greater than 65 years old. Finally, high-risk WM patients have more than two of these risk factors.
Treatment of Lymphoplasmacytic Lymphoma
Because WM is incurable, the goal of treatment is to improve quality-of-life. Treatment may or may not prolong survival but should certainly make the patient feel better. Minimal adverse effects are desired. As such, asymptomatic patients should be observed carefully, with treatment deferred until significant symptoms are present. Treatment should not be initiated simply for an elevated IgM protein level.
This watchful-waiting approach is the same treatment strategy recommended for other indolent NHLs. Indications for treatment include general patient symptoms (such as fever, night sweats, fatigue), painful lymphadenopathy, painful splenomegaly, severe anemia or thrombocytopenia due to bone marrow involvement, symptoms of hyperviscosity, peripheral neuropathy, renal insufficiency, or cryoglobulinemia.
There is no drug or combination of drugs that is considered standard first-line therapy for WM. Traditional chemotherapy drugs, such as chlorambucil, cyclophosphamide, cladribine, and fludarabine, all lead to initial response rates of 30 to 90%. Bone marrow suppression can be problematic, however, as most of these patients already have low blood counts related to their disease. Rituximab, a monoclonal antibody that specifically kills B-cell lymphomas, leads to a response in 60 to 80% of WM patients as first line therapy. It does not have the problem of causing bone marrow suppression, which makes it a more attractive first-line option in many patients. Close monitoring is still required, however, as a rapid increase in the IgM protein can occur at the start of therapy. Rituximab is often combined with chemotherapy and/or corticosteroids. The bottom line is that the choice of first-line therapy in WM is made based upon anticipated side effects in each individual patient.
Novel therapies under investigation include bortezomib, which disrupts cellular homeostatic mechanisms, the anti-angiogenesis agents thalidomide and lenalidomide, and alemtuzumab, a B-cell monoclonal antibody. Hematopoietic stem cell transplant (so-called bone marrow transplant) is the standard of care in patients with a good performance status who have recurrent or refractory aggressive lymphomas, such as diffuse large B-cell. In the case of recurrent indolent NHL, however, the role of bone marrow transplant is less clear. As such, bone marrow transplant is considered an investigational treatment for WM and should be done only in the setting of a clinical trial.
Supportive Care Issues
Infections due to bone marrow involvement with lymphoma and/or chemotherapy immune suppression are common in WM patients. This is especially true in patients receiving rituximab as part of their therapy. Prophylaxis with antibiotics may be appropriate in some, and patients should always contact their oncologist if they develop a fever. Recurrent infections in patients with WM may also be related to decreased amounts of normal antibodies in the blood. If this is the case, patients may receive monthly supplemental intravenous immunoglobulin (IVIG).
Hyperviscosity syndrome is treated with plasmapheresis (also called plasma exchange) to remove the excessive IgM protein in the blood. This is an effective treatment, as 80% of IgM is present in the blood vessels rather than in the tissues. Plasmapheresis is a temporary, symptomatic treatment only. Ultimately, control of the underlying WM leads to control of the symptoms of hyperviscosity.
AS discussed, IgM protein in the blood can interfere with the functioning of clotting factors and platelets. Normally, bleeding is mild, such as self-limited nosebleeds. Some patients, however, will require treatment with supplemental clotting factors. This usually involves intravenous transfusion of fresh frozen plasma or cryoprecipitate. Platelet transfusions are rarely required. As with hyperviscosity syndrome, control of the WM is necessary to control bleeding complications.
Although more common as a complication of CLL, autoimmune abnormalities may be present in patients with WM. This includes autoimmune hemolytic anemia (destruction of the red blood cells) and peripheral neuropathies. In addition to treating the underlying lymphoma, treatment of these autoimmune complications usually includes corticosteroids such as prednisone and/or IVIG.
